Q-Chem is a molecular modeling software package that contains some of the most advanced computational quantum chemistry methods available today. It is used to model atomic and molecular processes in a wide variety of disciplines, ranging from biological chemistry to materials science. The goal of this Phase II project is to develop and implement a general hybrid scheme to greatly extend the size and complexity of molecular systems that can be effectively modeled quantum mechanically with Q-Chem. Target systems include molecules containing tens of thousands of atoms, including enzymes, transition metal containing proteins, and catalysts of industrial importance. The new method will provide the user with the option of applying different computational methods to different regions of the molecule. Thus, a high-cost quantum mechanics (QM) based method can be applied to the critical area of the molecule (such as the active site of an enzyme) where accuracy is essential and a less-costly method can be applied to the rest of the molecular system. The result is that the user will be able to carry out highly accurate quantum mechanical based calculations with only minor increases in the computational cost. The formulism is completely general, maintains the original formulas and properties of each of the theories employed in the simulation, and is based on separation of the electron density matrix to more effectively treat the interface between the quantum mechanical and molecular mechanical regions. Furthermore, the proposed scheme is not limited to QM/MM hybrid simulations but rather is easily extended to QM/QM hybrid simulations. Accordingly, combined DFT/HF, DFT/SE, MP2/SE, and MP2/HF methods will also be developed. The new hybrid models will enable Q-Chem to reach a much larger market where high-level quantum modeling is desired but is currently prohibitively expensive. [unreadable] [unreadable]